title: mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia.
abstract: Pulmonary arterial vascular smooth muscle (PAVSM) cell proliferation is a key pathophysiological component of vascular remodeling in pulmonary arterial hypertension (PAH) for which cellular and molecular mechanisms are poorly understood. The goal of our study was to determine the role of mammalian target of rapamycin (mTOR) in PAVSM cell proliferation, a major pathological manifestation of vascular remodeling in PAH. Our data demonstrate that chronic hypoxia promoted mTOR(Ser-2481) phosphorylation, an indicator of mTOR intrinsic catalytic activity, mTORC1-specific S6 and mTORC2-specific Akt (Ser-473) phosphorylation, and proliferation of human and rat PAVSM cells that was inhibited by siRNA mTOR. PAVSM cells derived from rats exposed to chronic hypoxia (VSM-H cells) retained increased mTOR(Ser-2481), S6, Akt (Ser-473) phosphorylation, and DNA synthesis compared to cells from normoxia-exposed rats. Suppression of mTORC2 signaling with siRNA rictor, or inhibition of mTORC1 signaling with rapamycin and metformin, while having little effect on other complex activities, inhibited VSM-H and chronic hypoxia-induced human and rat PAVSM cell proliferation. Collectively, our data demonstrate that up-regulation of mTOR activity and activation of both mTORC1 and mTORC2 are required for PAVSM cell proliferation induced by in vitro and in vivo chronic hypoxia and suggest that mTOR may serve as a potential therapeutic target to inhibit vascular remodeling in PAH.
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Vera P
authors.initials: VP
authors.lastname: Krymskaya
authors.forename: Jennifer
authors.initials: J
authors.lastname: Snow
authors.forename: Gregory
authors.initials: G
authors.lastname: Cesarone
authors.forename: Irene
authors.initials: I
authors.lastname: Khavin
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Goncharov
authors.forename: Poay N
authors.initials: PN
authors.lastname: Lim
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Veasey
authors.forename: Kaori
authors.initials: K
authors.lastname: Ihida-Stansbury
authors.forename: Peter L
authors.initials: PL
authors.lastname: Jones
authors.forename: Elena A
authors.initials: EA
authors.lastname: Goncharova
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D010101:Oxygen Consumption; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat